The Specific Aim of this proposal is to test the feasibility of using a novel method of enhancing neuroplasticity for the purpose of producing clinically significant improvements in the ability of stroke patients to perform their activities o daily living (ADLs). One of the major goals of MicroTransponder is to translate pre-clinical findings of enhancing neuroplasticity into clinical use to help rehabilitate people with neurological deficits. Our method of enhancing neuroplasticity is pairing very short pulses of vagus nerve stimulation (VNS) with specific therapeutic exercises. This method is a novel application of VNS that is sharply distinct from the current clinical use of VNS for the treatment of refractory epilepsy and depression. For treatment of epilepsy and depression, VNS is given 24 hours per day seven days a week and the stimulation is not paired with any specific input. For our treatment, there is specific pairing of VNS with a task to be learned and VNS is only delivered while the patient is practicing the task. Ischemic stroke is a leading cause of adult disability in the US, with upper motor deficits being the primary cause of the disability. These disabilities prevent patients from performing ADLs, which makes them dependent on caregivers. This situation is associated with serious co-morbidities, including depression. In all, such patients suffer a serious loss in quality of life. Current rehabilitation techniques help some patients regain some degree of lost upper limb function; however, a much greater degree of recovery is still needed in order to allow patients to achieve the key goal of gaining independence. To address this unmet medical need, we are evaluating the method of pairing VNS with rehabilitative tasks in rat models of ischemic stroke. In preliminary findings using an endothelin-1 (ET-1) stroke model, we observed that VNS paired with an upper limb motor task resulted in full recovery of lost function, while rehabilitation without VNS generated only partial recovery with a sustained plateau of suboptimal function. However, there are several key issues that must still be addressed in order to support testing this method in stroke patients. We must show that VNS will generalize to more than one model of ischemic insult and that the results are long lasting. To achieve our Specific Aim, we will carry out the following Task: Task 1: Using a rat model of middle cerebral artery occlusion (MCAo), evaluate recovery of function of upper limb motor deficits in three groups of rats: Group 1: VNS paired with rehabilitation training, Group 2: VNS offset one hour before rehabilitation training (unpaired), and Group 3: VNS implant but no stimulation (sham control). We must find at least 80% greater recovery of function when VNS is paired with training than in the other groups. Further, recovery of function in animals that received VNS paired with training must maintain at least 90% of those gains for at least five weeks in the absence of subsequent training.